The reduction of the 6-keto group of certain morphinans is a necessary step in the preparation of many opiate-based compounds such as nalbuphine. Traditionally, the 6-keto group has been reduced using boron reducing agents, e.g., NaBH4, at reduced temperatures. See, for example, R. Van Gurp et al., Chemistry of Opium Alkaloids. Part XXIV, Synthesis of 7,8-didehydro-3,4-dimethoxy-17-methylmorphinan-6-one and the Regioselective Reduction of the Keto Function, Neth. Bulletin des Societes Chimiques Belges 96(4), pp. 325-9 (1987) and K. Uwai et al., Syntheses and Receptor-binding Studies of Derivatives of the Opioid Antagonist Naltrexone, Bioorg. & Med. Chem., 12, p. 417 (2004). For this synthetic route, the reduced temperatures provide the desired excess of the 6-α-hydroxy epimer. Depending on the temperature, the epimeric ratio can be as high as 99:1 6α:6β hydroxy at temperatures below −20° C. Higher temperatures tend to erode this ratio resulting in an increased percentage of the 6-β-hydroxy epimer. Other boron-derived reducing agents have improved on this ratio and have allowed the reaction to be conducted at more reasonable temperatures. See, for example, L. Malspeis et al., Metabolic Reduction of Naltrexone. I. Synthesis, Separation, and Characterization of Naloxone and Naltrexone Reduction Products and Qualitative Assay of Urine and Bile Following Administration of Naltrexone, α-Naltrexol, or β-Naltrexol, Res. Commun. Chem. Pathol. Pharmacol, 2(43) (1975); L. Olsen at al., Conjugate Addition Ligands of Opioid antagonists. Methacrylate Esters and Ethers of 6α-and 6β-naltrexol, J. Med. Chem., 33(2), pp. 737-41 (1990); and G. Koolpe et al., Opioid Agonists and Antagonists. 6-Desoxy-6-substituted Lactone, Epoxide, and Glycidate Ester Derivatives of Naltrexone and Oxymorphone, J. Med. Chem., 28(7), pp. 949-57 (1985).
Upon completion of the reaction and destruction of any excess reducing reagent, the reduced opiate is typically isolated by extraction. The isolation methods, however, typically fail to supply useful quantities of the desired compounds. Instead, the yields tend to be low and purification difficult. Repeated extractions using chloroform are normally necessary to liberate the product from the reaction. After the extraction process is complete, a lengthy distillation is necessary to remove the excess chloroform. The yields for the conversion process utilizing the boron reducing groups vanes widely, from about 50 to 90%. In addition, under certain conditions, crystallization of the product is essential to raise the epimeric purity.
Accordingly, a need exists for a convenient and efficient method of converting 6-keto morphinans to 6-α-hydroxy morphinans. This method should ensure high epimeric purity and also allow for simplified isolation of the desired compound.